Short-term neonatal and long-term neurodevelopmental outcome of children born term low birth weight

This study aimed to examine the impact of term LBW on short-term neonatal and long-term neurodevelopmental outcomes in children 5–7 years of age. This is a population-based cohort study that merged national data from the Korea National Health Insurance claims and National Health Screening Program for Infants and Children. The participants were women who gave birth at a gestational age of ≥ 37 weeks between 2013 and 2015 in the Republic of Korea, and were tracked during 2020 for the neurodevelopmental surveillance of their children. Among 830,806 women who gave birth during the study period, 31,700 (3.8%) of their babies weighed less than 2500 g. By Cox proportional hazard analysis, children aged 5–7 years who had LBW were associated with any developmental, motor developmental delay, cognitive developmental delay, autism spectrum, attention deficit hyperactivity disorders, and epileptic and febrile seizures.Children born with term LBW were more vulnerable to neurodevelopmental disorders at 5–7 years of age than those with normal and large birth weights. This study further substantiates counseling parents regarding the long-term outcomes of children being born underweight.


Data characteristics
This study was conducted by merging national data from the Korea National Health Insurance (KNHI) claims, National Health Screening Examination (NHSE), and National Health Screening Program for Infants and Children (NHSP-IC).In Korea, 97% of the population is enrolled in the KNHI program, and its claims database contains all their claims information.Therefore, this centralized database contains comprehensive information on diseases and their treatments except for non-insurance procedures.Using this database, we identified all pregnant women who delivered between January 1, 2013, and December 31, 2015.Subsequent developmental delay, motor developmental delay, cognitive developmental delay, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and epileptic and febrile seizures in their children up to 5-7 years were tracked until December 31, 2020.The KNHI system provides an NHSP-IC linked to maternal data for all neonates.Key components of the NHSP-IC include a health examination of the children, assessment of their gestational age at delivery, and measurement of birth weight.This study was approved by the Institutional Review Board of the Korea University Medical Center (No. 2023GR0196) which waved the requirement for informed consent for the following reason.All information was provided for the study after it had been anonymized; therefore, informed consent was not obtained from the participants.All methods were performed in accordance with the declaration of Helsinki.

Study population
A flowchart of patient enrollment is shown in Fig. 1.Birth weight was categorized as LBW < 2500 g, normal birth weight 2500-3999 g, and large birth weight ≥ 4000 g.Women who had a gestational age of ≥ 37 weeks were included.Among these, women who had multiple pregnancies, preterm births, fetal malformations, syndromes and other abnormalities allocated Q code in the International Classification of Disease-10th Revision (ICD-10), women whose children did not undergo the NHSP-IC, and missing values were excluded.Perinatal factors were obtained on maternal characteristics (age, type of delivery, pregnancy-induced hypertension, gestational diabetes (GDM), hypertension and diabetes mellitus (DM) diagnosed before pregnancy) and infant characteristics (sex and birthweight) using the KNHI claims dataset.In addition, the medical issues of the infants including transient tachypnea, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD) and birth asphyxia were identified.Underlying maternal and neonatal diseases were identified according to the ICD-10 codes.

Short-term complications in neonates
Cox proportional hazards models were used to estimate the adjusted HRs (aHRs) and 95% CIs for the development of short-term neonatal outcomes related to birth weight after adjustment for confounding factors (Table 3).Neonates with LBW had significantly higher rates of transient tachypnea (aHR 2. 34 www.nature.com/scientificreports/

Neurodevelopmental outcome stratified by birth weight
The neurodevelopmental outcomes related to the birth weight of the neonates were estimated using Cox proportional hazards models after adjustment for confounding factors (Table 4).LBW was associated with any developmental delay (aHR 1.36, 95% CI 1.29-1.44),motor developmental delay (aHR 1.31, 95% CI 1.22-1.42),cognitive developmental delay (aHR 1.43, 95% CI 1.33-1.54),ASD (aHR 1.76, 95% CI 1.59-1.95),ADHD (aHR 1.30, 95% CI 1.17-1.46),and epileptic and febrile seizures (aHR 1.14, 95% CI 1.10-1.18).There was no difference in neurodevelopmental outcomes between neonates with large and normal birth weights.Figure 2 shows Kaplan-Meier curves for the cumulative incidence of neurodevelopmental outcomes among the low, normal, and large birth weight groups.Up to 7 years of age, the cumulative incidences of motor, cognitive, and any developmental delays, in addition to ASD, ADHD, and epileptic and febrile seizures were significantly higher in the LBW group than in normal and large birth weight groups.

Discussion
This study examined the short-and long-term outcomes, including neurodevelopmental disorders, of babies with low, normal, and large birth weights using national population data.Children with LBW were not only susceptible to short-term complications but also suffered increasingly from motor, cognitive, and any developmental delays, ASD, ADHD, and epileptic and febrile seizures up to the age of 7.
LBW is a risk factor for neonatal morbidity and mortality, overall health, and developmental disorders 15 .However, previous studies have predominantly focused on the impact of LBW due to preterm birth, indicating that prematurity itself is a major cause of developmental disorders 16 , and research on LBW infants born at term has focused on IQ, learning, and behavior 17,18 .In addition, the definitions of small for gestational age (SGA) or fetal growth restriction, children age at assessment and outcome variables were varied with or without deficits in cognitive and learning abilities, and occurrence of attention problems 19 .Few studies have targeted the Asian population in this aspect.
Consistent with our findings, a Norwegian population study recently demonstrated a highly significant dose-response association between birthweight and cerebral palsy, vision/hearing disability, intellectual impairment, schizophrenia, epilepsy, ASD, and behavioral disorders such as ADHD 20 .Sacchi et al. performed a metaanalysis of 2230 children born at term who had intrauterine growth restriction or were SGA and demonstrated that they had lower cognitive scores than those who were appropriate for gestational age 15 .However, the other studies demonstrated no differences or mixed results in developmental outcomes, including school performance, attention problems, and psychological symptoms [21][22][23] .This could be attributed to methodological limitations due to multiple contributing factors, such as different ethnic backgrounds, social interactions, and economic aspects.Given the impact of ethnic differences on LBW infants, our study's specific focus on the Asian population is of particular importance.
Poor growth, maternal malnutrition, poverty, stress, infections such as malaria and HIV, diarrhea, environmental toxins, psychosocial factors such as learning opportunities, caregiver interaction, violence, and maternal depression can contribute to the deterioration child brain functioning 24,25 .However, the exact physiological mechanisms behind LBW and its effects on development are not yet fully understood due to the complexity of the causal pathways involved.One possible theory is related to fetal programming.Abnormal fetal growth is a sign of substantial alterations in fetal programming.The fetus adapts and survives in the uterus by slowing its growth.Defective placentation is a phenomenon that results in poor fetal growth, and may cause hypoxemia, inflammation, undernutrition, and endocrine dysregulation, which could impair normal brain development 25,26 .It could also lead to chronic hypoxia, which causes poor growth and consequently cerebral injury, especially in the primary sensory and forebrain motor systems, resulting in cognitive, motor, and attentional deficits 27 .Barker's theory supports the concept of fetal programming, indicating that individuals born under conditions of inadequate nutrition during pregnancy face a higher risk of ischemic heart disease and mortality as adults 28 .This evidence has been further expanded in recent years, suggesting that children born in suboptimal conditions in the uterus may experience increased health issues.
Cerebral microstructural and metabolic changes were evident in fetal brain magnetic resonance imaging of LBW infants, and this might cause abnormal neurodevelopment 29 .Placental dysfunction, a situation which the fetus has a limited transport of nutrients and oxygen also explains the association between LBW and ASD.Consistent with our finding that the ASD rate was significantly increased in LBW infants, a meta-analysis including www.nature.com/scientificreports/more than 8 million participants demonstrated a significant association between infants who were SGA and the risk of ASD 30 .
Morbidities associated with LBW such as RDS and BPD may cause poor neurodevelopment 31,32 .Hypoxia caused by short-term respiratory problems in the neonatal period can interfere with normal brain development.As demonstrated by our data, LBW infants are more likely to suffer from complications during the neonatal period owing to the suboptimal oxygen levels that can damage their rapidly growing neurons and prevent them from forming new connections.Despite our analysis adjusting for neonatal complications, there was still an increased rate of developmental delay in LBW infants.
There have been limited studies on the association between LBW and tics and stereotypic disorders, which are highly complex and multifactorial in etiology.A study on the Korean population reported associations between tics and perinatal factors and revealed no association with LBW 33 which is consistent with our findings.However the age of onset of tics and stereotypic disorders is usually 4-6 years, and since our study included children aged 5-7 years, there are limitations in establishing an association between LBW and tics and stereotypic disorders.
Our study findings on the relationship between LBW infants born on term and developmental outcomes prompt the identification of risk factors and early intervention.Several modifiable factors in the early environment may have long-term effects on health and cognitive function.In a British study, the learning environment (parental reading and interest in education) influenced cognitive development independent of birth weight and social background 34 .A prospective study suggested that stimulation at home may improve neurodevelopment in LBW children, especially during the early period 35 .According to a study on Korean adopted children, developmental outcomes may differ within the first 2 years depending on environmental factors and nutritional supply alone 36 .This emphasizes the significance of the early identification of children who are at risk of cognitive and motor deficits, closely monitoring their development and intervening promptly and effectively to enhance their developmental abilities.
Parents typically do not consider their LBW infants born on term to be at a risk of developmental disadvantages, and their postnatal care is underestimated.Therefore, it is crucial for healthcare professionals to educate parents about the importance of early screening and evaluation of these infants to ensure their healthy development.
This study boasts several notable strengths, primarily deriving from a population-based cohort, which offers the advantage of comprehensive and extended follow-up.Furthermore, to mitigate potential sources of bias, the study meticulously identified and controlled for numerous underlying risk factors pertaining to perinatal characteristics.Nonetheless, it is imperative to approach our findings with a degree of caution, recognizing several limitations.First and foremost, the neurodevelopmental outcomes of the children under scrutiny in this research were determined based on ICD-10 codes extracted from insurance claims data.Consequently, questions regarding the reliability and accuracy of these diagnoses within this database may arise detailed diagnostic methods used for developmental delay have not been reviewed.However, a recent study showed a 78.1-88.7%sensitivity and 100% specificity when comparing the diagnoses obtained from insurance claims data with the verified diagnoses documented in patient medical records 37 .Furthermore we encountered limitations in accessing essential information regarding influential factors of growth and neurodevelopment, such as socioeconomic status, cognitive and motor stimulation during early life, parent BMI and education, social environment, and nutritional status after birth.Prospective studies considering these factors are needed to further investigate the association between birth weight and neurodevelopmental outcomes.
In summary, the findings of this study show that developmental delay, ASD, ADHD, and epileptic and febrile seizures were increased in LBW infants born at term.These findings support the notion that LBW infants born at term need timely evaluation of their neurodevelopment because early detection and intervention are key to improved quality of life.The findings of this study need to be confirmed in a prospective study.Furthermore, studies on the mechanisms involved in neurodevelopment associated with LBW should be conducted.

Figure 2 .
Figure 2. Kaplan-Meier curves for the cumulative incidence of cognitive, motor, and any developmental delays, ASD, ADHD, and epileptic and febrile seizures among the groups.ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder.

Table 1 .
Diagnosis based on International Classification of Disease-10 codes.

Table 3 .
Neonatal outcome of LBW, normal birth weight and large birth weight.

Table 4 .
Neurodevelopmental outcome of LBW, normal birth weight and large birth weight.